Use of phospholipids in peritoneal dialysis

ABSTRACT

The efficiency of ultrafiltration in continuous ambulatory peritoneal dialysis (CAPD) is improved by administering a composition comprising at least one surface active phospholipid (SAPL) in powder form, especially as a mixture of phosphatidyl choline and phosphatidyl glycerol, into the peritoneal cavity before commencing CAPD or between CAPD sessions. The SAPL composition may be introduced during surgery to prepare a patient for CAPD and/or subsequently through the incision for the CAPD catheter, or through the catheter itself, between CAPD sessions when one batch of dialysis fluid has been removed and before a fresh batch is supplied.

This invention relates to the use of surface active phospholipids (SAPL)to improve the efficiency of ultrafiltration (UF) in patients oncontinuous ambulatory peritoneal dialysis (CAPD).

In 1985, Grahame et al (Perit. Dial. Bull. 1985; 5:109-111) identifiedsurface-active phospholipids (SAPL) within the peritoneal cavities ofpatients on continuous ambulatory peritoneal dialysis (CAPD). Thisfollowed the earlier discovery of SAPL in the pleural cavity by Hills etal (J. Appl. Physiol. 1982; 53:463-469) and forming an oligolamellarlining which lubricates the pleural mesothelium. A similar lining hassince been demonstrated reversibly bound (adsorbed) to peritonealmesothelium; while the efficacy of adsorbed peritoneal SAPL to act as aboundary lubricant and release agent has been demonstrated by standardphysical tests (Chen and Hills; Aust. N. Z. J. Surg. 2000; 70:443-447).

Grahame's discovery led to a somewhat tenuous link being establishedbetween any reduction in ultrafiltration (UF) in CAPD patients and anincreasing loss of SAPL in their spent dialysate (Di Paolo et al; Perit.Dial. Bull. 1986; 6:44-45). This finding led to a spate of clinicaltrials in the late 1980s and early 1990s in which peritoneal surfactantwas replenished in patients by spiking dialysis fluid with exogenousSAPL. The wide spectrum of outcomes ranged from several totally negativeresults to others where UF was increased. In the few studies wheretheory was discussed, the mechanism was generally attributed to a rathernebulous role for SAPL in eliminating a stagnant liquid layer adjacentto the mesothelium (Breborowicz et al; Perit. Dial. Bull. 1987; 7:6-9)although, in specific studies, such a fluid boundary layer has beendispelled as offering no significant resistance to mass transfer ofsolutes in PD (Flessner et al; Am. J. Physiol. 1985; 248:F413-424).Subsequently a study by Beavis et al (J. Am. Soc. Nephrol. 1993;3:1954-1960) held that there is no relationhsip between dialysatephospholipid levels and the adequacy of UF, and that there was nosupport for a rationale for intraperitoneal phosphatidyl cholineadministration in CAPD patients with poor UF.

The present invention starts from the knowledge (Chen and Hills, above)that there is a lining of surface active phospholipid (SAPL) reversiblybound (adsorbed) to normal peritoneal mesothelium which acts as aboundary lubricant and release agent preserving mechanical integrity ofthis epithelial surface. The present invention is based on the findingthat indigenous peritoneal SAPL is capable of imparting semipermeabilityto a surface to which it is adsorbed, leading to the conclusion thatadsorbed SAPL imparts to peritoneal mesothelium the semi-permeabilityvital for UF and that any deficiency in SAPL can compromise UF.

The present invention is based on the use of powder compositions ofphospholipids and liquid, semi-liquid or pasty compositions ofphospholipids dispersed in a physiologically acceptable carrier topromote UF in CAPD patients by administering the compositions directlyinto the peritoneal cavity or by addition of the compositions to thedialysate used in CAPD.

SAPL powders as described in WO 99/51244 (Britannia) are easilyadministered into body cavities such as the peritoneum by simple“puffers” or other gas stream delivery devices, and the indicated SAPLsspread rapidly into inaccessible areas. Other suitable compositions arethe liquid and paste SAPL compositions disclosed in U.S. Pat. No.6,133,249 (Hills).

In one aspect the present invention provides a method of improving theefficiency or reducing deficiency of ultrafiltration in continuousambulatory peritoneal dialysis which comprises administering acomposition comprising at least one SAPL in powder form or dispersed ordissolved in a physiologically acceptable non-volatile carrier liquidinto the peritoneal cavity before commencing CAPD or between CAPDsessions.

Thus the SAPL may be introduced during surgery to prepare a patient forCAPD; and/or subsequently through the incision for the CAPD catheter, orthrough the catheter itself, between CAPD sessions when one batch ofdialysis fluid has been removed and before a fresh batch is supplied.

In another aspect the present invention provides a method of improvingthe efficiency or reducing deficiency of ultrafiltration in continuousambulatory peritoneal dialysis which comprises administering acomposition comprising at least one SAPL in powder form or dispersed ordissolved in a physiologically acceptable non-volatile carrier liquid(other than saline) into the dialysis fluid before commencing a CAPDsession.

In this aspect the SAPL composition is mixed with the dialysis fluid anddelivered with the dialysis fluid via the catheter provided for thefluid in a CAPD session.

In another aspect the present invention provides the use of at least oneSAPL in powder form or dispersed or dissolved in a physiologicallyacceptable non-volatile carrier liquid (other than saline) to prepare amedicament for reducing improving the efficiency or reducing deficiencyof ultrafiltration in continuous ambulatory peritoneal dialysis.

Examples of SAPLs which may be used in this invention includephosphatidylcholine (PC), in particular as diacyl phosphatidylcholines(DAPCs), e.g. dioleyl phosphatidylcholine (DOPC); distearylphosphatidylcholine (DSPC) and dipalmnitoylphosphatidyl choline (DPPC).A spreading agent may be included which functions to reduce the meltingpoint of a DAPC so that it rapidly spreads as a thin film at normal bodytemperature. Suitable spreading agents include phosphatidyl glycerols(PG); phosphatidyl ethanolamines (PE); phosphatidyl serines (PS) andphosphatidyl inositols (PI). Another useful spreading agent ischlorestyl palmitate (CP).

The above spreading agents, especially PG, are believed to enhance orpotentiate the binding of the DAPC, especially the DPPC, to anepithelial surface. However compositions based on DPPC alone maysometimes be as effective as compositions based on DPPC/PG.

Also pastes prepared by dispersing coarse SAPL particles, for examplearound 10 μm in size, may be more effective than when using fine SAPLparticles, such as around 5 μm in size. More generally, the powderedSAPL may have a particle size in the range of 0.5 to 100 μm, moresuitably of 0.5 to 20 μm, preferably 0.5 to 10 μm.

Most suitably the dry SAPL composition is prepared fromphosphatidylcholine (PC) and phosphatidyl glycerol (PG), but theinvention is not limited solely to use of these lipids. Naturalendogenous materials contain neutral lipids, fats, inorganic ions etc,all of which are integral to their form and function, and inclusion ofthese in formulations for use in the invention is not excluded.Preferred SAPL compositions are synthetic dipalmitoylphosphatidylcholine (DPPC) co-precipitated from a common solvent systemwith PG in the weight ratio of 6:4 to 8:2, especially about 7:3. Thecomposition is advantageously administered as a dry powder since itspreads extremely rapidly on water.

The phospholipids used in accordance with the invention have acylsubstituents on the phosphatidyl groups. As in their naturalcounterparts, the acyl groups may comprise identical or different,saturated or unsaturated acyl radicals, generally C14-22, especiallyC16-20, acyl radicals. Thus the phospholipids may comprise, by way ofacyl radicals, the saturated radicals palmitoyl C16:0 and stearoyl C18:0and/or the unsaturated radicals oleoyls C18:1 and C18:2. Diacylsubstitution is preferred and the phospholipids used in the compositionsin accordance with the invention more particularly comprise twoidentical saturated acyl radicals, especially dipalmitoyl anddistearoyl, or a mixture of phospholipids in which such radicalspredominate, in particular mixtures in which dipalmitoyl is the majordiacyl component. Thus PC and PG may be used may be used with the samediacylphosphatidyl profile as in PC and PG extracted from human oranimal or vegetable sources, but if synthetic sources are used thedipalmitoyl component may predominate, as in the DPPC mentioned above.

As also mentioned above, the SAPL compositions are most preferablyprotein free, but in some circumstances the presence of proteins andadjuvants, especially naturally occurring materials from plant or animalsources, or synthetically derived, may be tolerated, especially proteinsassociated with PC and PG in vivo in conjunction with a dry powderedformulation for use in this invention. Especially apoprotein Bmarginally improves SAPL adsorption, and so may be useful if toleratedin SAPL compositions for human use.

DPPC can be prepared synthetically by acylation ofglycerylphosphorylcholine using the method of Baer & Bachrea—Can. J. ofBiochem. Physiol 1959, 37, page 953 and is available commercially fromSigma (London) Ltd. The PG may be prepared from egg phosphatidyl-cholineby the methods of Comfurions et al, Biochem. Biophys Acta 1977, 488,pages 36 to 42; and Dawson, Biochem J. 1967, 102, pages 205 to 210, orfrom other phosphatidyl cholines, such as soy lecithin.

When co-precipitated with DPPC from a common solvent such as chloroform,PG forms with DPPC a fine powder which spreads rapidly over the surfacesof the airways and lungs. The most preferred composition of theinvention contains DPPC and a phosphatidyl glycerol derived from eggphosphatidyl choline, which results in a mixture of C16, C18 (saturatedand unsaturated) and C20 (unsaturated) acyl groups.

The SAPL compositions preferably used in accordance with the presentinvention are finely-divided, solid powders and are described in detailin our co-pending PCT applications WO 99/27920 and WO 00/30654, thewhole contents of which are incorporated by reference. However insummary, our above applications indicate that an important feature ofthe SAPL compositions that are usable in the present invention is thatthey are in the form of a powder, that is, it is in solid form. The“dry” surfactant has a high surface activity.

When the SAPL is dispersed or dissolved in a carrier liquid, the carrierliquid is typically one which is substantially non-volatile or onlysparingly volatile at body temperature. Suitable carriers includephysiologically acceptable glycols, especially propylene glycol,polyethylene glycols and glycerol.

The SAPL may be dispersed in the carrier so as to form liquid,semi-liquid or pasty compositions. Semi-liquid or paste compositions arepreferred.

Pastes can be prepared by simply dispersing a SAPL powder in thecarrier, or when appropriate dissolving the SAPL(s) in heated carrierand allowing the SAPL(s) to precipitate as a powder on cooling,preferably at a loading that will form a paste. A thick paste of theSAPL and carrier is ideal to apply to open wounds to which it adhereswell. It enables a much higher concentration of the SAPL to be appliedto the incision site.

Propylene glycol is especially effective as a carrier because at roomtemperature SAPL may be dispersed in it as a paste, but at bodytemperature a mobile solution is formed. A paste of 400 mg/ml of DPPC inpropylene glycol has given 93% protection against adhesions in surgicaltests, as described in the experiments below.

Also polyethylene glycols may be prepared which are waxy solids at roomtemperature and liquids at body temperature, such as for example PEG600.

Various dispersions of SAPLs in propylene glycol are described in U.S.Pat. No. 6,133,249, the entire contents of which are incorporated hereinby reference. Similarly the powder compositions of WO 99/51244 may bedispersed in a carrier such as propylene glycol, and the entiredisclosure of WO 99/51244 is also incorporated herein by reference.

In whichever form it is delivered, preferably the SAPL composition hastwo components. Suitably the first component of the SAPL comprises oneor more compounds selected from the group consisting of diacylphosphatidyl cholines. Examples of suitable diacyl phosphatidyl cholines(DAPCs), are dioleyl phosphatidyl choline (DOPC); distearyl phosphatidylcholine (DSPC) and dipalmitoyl phosphatidyl choline (DPPC). Mostpreferably, the first component is DPPC.

The second component may comprise one or more compounds selected fromthe group consisting of phosphatidyl glycerols (PG); phosphatidylethanolamines (PE); phosphatidyl serines (PS); phosphatidyl inositols(PI) and chlorestyl palmitate (CP).

Phosphatidyl glycerol (PG) is a preferred second component. PG is also apreferred second component because of its ability to form with the firstcomponent, especially PC and particularly DPPC, a very finely-divided,dry powder dispersion in air.

The composition advantageously comprises a diacyl phosphatidyl cholineand a phosphatidyl glycerol. The phosphatidyl glycerol is advantageouslya diacyl phosphatidyl glycerol. The acyl groups of the phosphatidylglycerol, which may be the same or different, are advantageously eachfatty acid acyl groups which may have from 14 to 22 carbon atoms. Inpractice, the phosphatidyl glycerol component may be a mixture ofphosphatidyl glycerols containing different acyl groups. Thephosphatidyl glycerol is expediently obtained by synthesis from purifiedlecithin, and the composition of the acyl substituents is then dependenton the source of the lecithin used as the raw material. It is preferredfor at least a proportion of the fatty acid acyl groups of thephosphatidyl glycerol to be unsaturated fatty acid residues, forexample, mono- or di-unsaturated C18 or C20 fatty acid residues.

Preferred acyl substituents in the phosphatidyl glycerol component arepalmitoyl, oleoyl, linoleoyl, linolenoyl and arachidonoyl. Themedicament preferably comprises dipalmitoyl phosphatidyl choline andphosphatidyl glycerol, with the phosphatidyl moiety of the phosphatidylglycerol advantageously being obtainable from the phosphatidyl moiety ofegg lecithin.

The compositions are administered preferably in a dry, finely-dividedstate, using a delivery device such as described in our above co-pendingapplications, or by directly introducing the aerosolised powder, e.g. bya tube which may be coated to aid transport of SAPL, into the peritonealcavity.

While not wishing to be limited to the following theory it is believedthat, when absorbed (reversibly bound) to the peritoneal mesothelium,SAPL provides a semi-permeable membrane by which the desired dialsysisis implemented. The predicated deficiency of SAPL which contributes topoor UF leads to a deficiency in this absorbed semi-permeable lining.This situation may be corrected by administering exogenous SAPL,advanatgeously in a form which displays two properties. First it spreadsrapidly over the surface of the incumbent fluid for widespreaddistribution throughout the peritoneal cavity. Secondly, it then absorbsto the epithelial surface to repair/fortify the semi-permeable barriercomprising similar material.

It is highly desirable that the SAPL should not break down quickly atthe surgical site in the body. One of the factors which will reduce thelife of a lining or coating of SAPL will be the presence of enzymes,such as phospholipase A, capable of digesting DPPC and/or PG. Suchenzymes only attack the laevorotatory (L) form, which constitutes thenaturally occurring form. Therefore, it may be preferable to use thedextrorotatory (D) form of the SAPL(s) or at least a racemic mixture,which is obtained by synthetic routes.

The compositions may also include preservatives where appropriate, suchas fungicides, bactericides and anti-oxidants.

The present invention is supported by the following experimental work.

Introduction

It has been previously demonstrated that there is a lining of surfaceactive phospholipid (SAPL) reversibly bound (adsorbed) to normalperitoneal mesothelium which acts as a boundary lubricant and releaseagent preserving mechanical integrity of this epithelial surface. Inreviewing clinical trials of the use of SAPL (alias “surfactant”) torestore ultrafiltration (UF) in patients on peritoneal dialysis (PD), wehave speculated that the SAPL lining might also be imparting thesemi-permeability vital for UF.

In evaluating this hypothesis, SAPL harvested from the spent dialysateof 5 patients with normal UF has been deposited on to a porous inertmedium and the resulting 7 ‘membranes’ clamped in an Ussing chamber usedas an osmometer. In every ‘membrane’ a clinical concentration of glucose(2.5%) was able to induce a statistically significant osmotic pressurewhen dialysed against saline. This proves that human peritoneal SAPL hasthe physical capability to impart semi-permeability when adsorbed to asurface. This could also explain the high permeability of the naturalmembrane to lipophilic substances in PD.

We have also demonstrated how synthetic SAPL in the form ofdipalmitoylphosphatidylcholine (DPPC) and its admixture withphosphatidyl glycerol (pumactant) imparts greater osmotic pressure anddoes so in proportion to the glucose gradient. Both pumactant and DPPCin various physical forms have been widely used for two decades withcomplete safety in the treatment of the respiratory distress syndrome innewborns. As a very fine powder, pumactant offers a potential role inrestoring UF if applied during the interdialytic interval.

The question of formulation of exogenous SAPL in restoringultrafiltration is discussed as a complex physico-chemical compromisebetween the higher surface activity of saturated PC and its lowersolubility in water.

Materials and Methods

Principle

The mechanical base for ‘the membrane’ is a fine-pore filter paperproven to be totally permeable to glucose, urea and physiologicallyrelevant ions. SAPL is then deposited as a thin coating and theresulting membrane clamped between the two compartments of an Ussingchamber to form an osmometer. Any osmotic pressure (ΔP) generatedbetween the compartments is measured as the difference in hydrostaticpressure needed to balance ΔP and stop further osmosis—see FIG. 1. TheSAPL is derived from spent dialysate from CAPD patients with normal UFand compared with synthetic surfactants envisaged as possible sources ofreplenishment of indigenous SAPL where UF is inadequate. The drivingforce for generating an osmotic pressure is provided by glucose inconcentration gradients used clinically to induce and control UF inCAPD.

Materials

The synthetic surface-active phopholipid (SAPL) was either dipalmitoylphosphatidylcholine (DPPC) purchased from Lipoid GmbH (Ludwigshafen,Germany) or pumactant provided by Britannia Pharmaceuticals Ltd(Redhill, UK). Human peritoneal SAPL was extracted from the spentdialysate of patients exhibiting normal UF using the Folch method (J.Biol. Chem. 1957; 226:497-509). All chemical reagents (chloroform,methanol and acetone) were at least AR grade and purchased from AJAXChemicals (Auburn, NSW, Australia) or BDH Laboratory Supplies (Poole,UK). Saline and Dianeal-2 dialysis fluids with glucose concentrations of1.5%, 2.5% and 4.25% (Baxter Healthcare, Old Toongabbie, NSW, Australia)provided the concentration gradients for generating osmotic pressure.Dialysis fluid with a glucose concentration of 3.4% was made byproportionally mixing two different dialysis fluids (with glucoseconcentrations of 2.5%; and 4.25%).

Methods

SAPL membranes were made by applying equal volumes of SAPL in chloroformsolution on to both sides of a filter paper (0.2 μm, white nylon,Millipore Corporation, Bedford, USA). Osmotic pressure was measured byclamping the SAPL membranes between the two compartments of an Ussingchamber (Jim's Instrument Manufacturing, Inc., Iowa, USA). Osmoticpressure was measured as the difference in hydrostatic pressure of thecompartments needed to stop further water transmission across themembrane. The total capacity and contact area of chambers areapproximately 0.7 ml and 0.44 cm². SAPL (2.36 mg of DPPC, pumactant orhuman peritoneal SAPL) and 3.78 mg SAPL (DPPC or pumactant) were usedfor different experiments. Two vertical tubes with inner diameters of1.2 mm were connected to the side, of each for measuring osmoticpressure. In the experiments, the left compartment was always filledwith saline and the right side with test solution (Dianeal-2 dialysisfluids with different glucose concentrations). The device is illustratedin FIG. 1. At the beginning of the experiment the fluid heightsindicating pressure were set the same on both sides of the membrane. Thewhole device was kept at 37° C. in a water bath and the fluid heightsindicating pressure difference were measured and recorded until therewas no further movement of fluid. At the end of each experiment theosmotic pressure was recorded as the difference in heights between thetwo fluid columns. The mean and S.E.M. were calculated for every groupof data and the one-way ANOVA test was used for statistical analysis.

The whole study was divided into five sections:

Section I:

Measurement of osmotic pressure produced by dialysing saline againstDianeal-2 dialysis fluids with 2.5% glucose concentrations against DPPC(2.36 mg per preparation) membrane (N=8).

Section II:

Measurement of osmotic pressure produced by dialysing saline againstDianeal-2 dialysis fluid with 2.5% glucose concentration againstpumactant (2.36 mg per preparation) membrane (N=8).

Section III:

Measurement of osmotic pressure produced by dialysing saline againstDianeal-2 dialysis fluid with 2.5% glucose concentrations usingextracted human peritoneal SAPL (2.36 mg per preparation) membrane(N=7).

Section IV:

Measurement of osmotic pressure produced by dialysing saline againstDianeal-2 dialysis fluids with different glucose concentrations (1.5%,2.5%, 3.4% and 4.25%) against DPPC (3.78 mg per preparation) membrane(N=8).

Section V:

Measurement of osmotic pressure produced by dialysing saline againstDianeal-2 dialysis fluid with different glucose concentrations (1-5%,2.5%, 3.4% and 4.25%) using pumactant (3.78 mg per preparation) membrane(N=8).

Results

In all experiments an osmotic pressure was generated by dialysing anyhypertonic dialysate against saline. The results from Sections I, II andIII are given in FIG. 2 while those from Sections IV and V are comparedin FIG. 3. The features of these results can be listed as follows:

1. In 7 runs, each using the pooled SAPL harvested from 5 exchanges, anosmotic pressure was always generated by Dianeal-2.

2. Synthetic SAPL was more effective than indigenous peritoneal SAPLwith pumactant more effective than DPPC at the same (2.36 mg)thickness—see FIG. 2.

3. Thicker membranes (3.78 mg DPPC) were more effective than thinnermembranes (2.36 mg DPPC),—see FIG. 2.

4. For the same membrane thickness and composition, the osmotic pressureincreased with the glucose driving force for osmosis—see FIG. 3—aspredicted by the van't Hoff equation governing osmosis.

5. Pumactant was more effective than pure DPPC at each glucoseconcentration. At glucose concentrations of 2.5% and 3.4%, pumactantmembranes generated statistically significant higher osmotic pressuresthan DPPC membranes (p<0.05).

Discussion

Although the results of this study show convincingly that humanperitoneal SAPL imparts semi-permeability to an inert porous base, itdoes not prove conclusively that it necessarily does the same toperitoneal mesothelium in vivo.

However, there are many factors which support this hypothesis. Firstlywe have previously demonstrated by epifluorescence microscopy that thereis a lining of SAPL adsorbed to parietal peritoneum which is probablyoligolamellar in nature, resembling similar linings adsorbed to pleuralmesothelium. Secondly, oligolamellar layers of SAPL in the form ofliposomes have long been known to be semi-permeable to suchlow-molecular weight solutes as NaCl. Thirdly, there is the evidencefrom clinical trials that there is a association between reduction of UFin PD and loss of SAPL in dialysate. It could be argued that thequantity recovered from spent dialysate does not necessarily reflect theamount of SAPL adsorbed to parietal mesothelium which surface accountsfor 85% of dialysis. However we have demonstrated that exogenous SAPL inthe form of radiolabelled DPPC does indeed adsorb to parietalmesothelium. This raises the issue of whether the administration ofexogenous SAPL should be employed for the restoration of UF in patientswho have lost that capability and what insight the adsorption theory mayoffer in the formulation of exogenous SAPL for this purpose. Inaddition, an SAPL barrier would help to explain why the peritonealmembrane is an order of magnitude more permeable to lipid-solublesubstances than to other solutes.

In attempting to review the many clinical trials of SAPL in improvingUF, the most frustrating aspect was the lack of physico-chemicalinformation on the widely diverse range of formulations which have beentested. Adsorption is a specialised branch of physical chemistry inwhich the Langmuir isotherm relates the quantity of a substance adsorbedto its concentration in the adjacent fluid phase. The two parametersmost desirable for high adsorption of any substance to a solid surfaceare high surface activity and high solubility in the adjacentphase—dialysate in the case of PD. Hence we selected DPPC as one of ourexogenous surfactants because it is generally regarded as the mostsurface-active phospholipid. This did indeed display bettersemi-permeability when used in the Ussing chamber as displayed in FIG.2. Unfortunately it is highly insoluble in water as demonstrated by acritical micelle concentration as low as 5×10⁻¹⁰ Molar (20). In order tocircumvent this problem, and largely to improve spreading, DPPC has beenused as an intimate mixture with PG (pumactant) in the use of surfactantin treating neonates born with the respiratory distress syndrome. Henceit could be fortuitous that not only is this mixture easier to dispensein aqueous fluids, but it has demonstrated the best results in itsability to impart semi-permeability—see FIG. 3. This is encouragingbecause, when applied as a fine dry powder to the peritoneum, it offeredexcellent results in preventing surgical adhesions. It would need to beadsorbed strongly to peritoneal mesothelium in order to act as aneffective boundary lubricant and release (anti-stick) agent protectingthe peritoneum. This raises the possibility of using the interdialyticinterval as an opportunity to replenish SAPL, adsorbed to peritonealmesothelium and hence restore ultrafiltration—whether prescribed as adry powder (e.g. pumactant) or dispensed in dialysate.

In conclusion, there is good evidence that adsorbed surface activephospholipid is providing the semi-permeability of the mesothelium vitalfor ultrafiltration, this mechanism offering a new physico-chemicalapproach to the formulation of SAPL for restoring ultrafiltration as setout in the present invention.

1. A method of improving the efficiency or reducing deficiency ofultrafiltration in continuous ambulatory peritoneal dialsysis whichcomprises administering a composition comprising at least one SAPL inpowder form or dispersed or dissolved in a physiologically acceptablenon-volatile carrier liquid into the peritoneal cavity before commencingCAPD or between CAPD sessions.
 2. A method of improving the efficiencyor reducing deficiency of ultrafiltration in continuous ambulatoryperitoneal dialysis which comprises administering a compositioncomprising at least one SAPL in powder form or dispersed or dissolved ina physiologically acceptable non-volatile carrier liquid (other thansaline) into the dialysis fluid before commencing a CAPD session.
 3. Useof at least one SAPL in powder form or dispersed or dissolved in aphysiologically acceptable non-volatile carrier liquid (other thansaline) to prepare a medicament for reducing improving the efficiency orreducing deficiency of ultrafiltration in continuous ambulatoryperitoneal dialysis.
 4. Use or method according to claim 1 in the SAPLis selected from diacyl phosphatidylcholines (DAPCs), such as dioleylphosphatidylcholine (DOPC); distearyl phosphatidylcholine (DSPC) anddipalmitoyl phosphatidylcholine (DPPC).
 5. Use or method according toclaim 4 in which the SAPL composition further includes a spreading agentsuch as a phosphatidyl glycerol (PG), phosphatidyl ethanolamine (PE),phosphatidyl serine (PS), phosphatidyl inositol (PI) or chlorestylpalmitate (CP).
 6. Use or method according to claim 1 in which the SAPLcomposition is a mixture of phosphatidylcholine (PC) and phosphatidylglycerol (PG).
 7. Use or method according to claim 6 in which the SAPLcomposition is a mixture of dipalmitoyl phosphatidylcholine (DPPC), or aphosphatidylcholine blend (PC) which is predominantly dipalmitoylphosphatidylcholine (DPPC), and phosphatidyl glycerol (PG).
 8. Use ormethod according to claim 1 in which the carrier is glycerol, propyleneglycol, or a polyethylene glycol.
 9. Use or method according to claim 8in which the carrier is propylene glycol.
 10. Use or method according toclaim 1 in which the SAPL/carrier is in the form of a paste.
 11. Use ormethod according to claim 2 in the SAPL is selected from diacylphosphatidylcholines (DAPCs), such as dioleyl phosphatidylcholine(DOPC); distearyl phosphatidylcholine (DSPC) and dipalmitoylphosphatidylcholine (DPPC).
 12. Use or method according to claim 3 inthe SAPL is selected from diacyl phosphatidylcholines (DAPCs), such asdioleyl phosphatidylcholine (DOPC); distearyl phosphatidylcholine (DSPC)and dipalmitoyl phosphatidylcholine (DPPC).
 13. Use or method accordingto claim 11 in which the SAPL composition further includes a spreadingagent such as a phosphatidyl glycerol (PG), phosphatidyl ethanolamine(PE), phosphatidyl serine (PS), phosphatidyl inositol (PI) or chlorestylpalmitate (CP).
 14. Use or method according to claim 12 in which theSAPL composition further includes a spreading agent such as aphosphatidyl glycerol (PG), phosphatidyl ethanolamine (PE), phosphatidylserine (PS), phosphatidyl inositol (PI) or chlorestyl palmitate (CP).15. Use or method according to claim 2 in which the SAPL composition isa mixture of phosphatidylcholine (PC) and phosphatidyl glycerol (PG).16. Use or method according to claim 3 in which the SAPL composition isa mixture of phosphatidylcholine (PC) and phosphatidyl glycerol (PG).17. Use or method according to claim 15 in which the SAPL composition isa mixture of dipalmitoyl phosphatidylcholine (DPPC), or aphosphatidylcholine blend (PC) which is predominantly dipalmitoylphosphatidylcholine (DPPC), and phosphatidyl glycerol (PG).
 18. Use ormethod according to claim 16 in which the SAPL composition is a mixtureof dipalmitoyl phosphatidylcholine (DPPC), or a phosphatidylcholineblend (PC) which is predominantly dipalmitoyl phosphatidylcholine(DPPC), and phosphatidyl glycerol (PG).
 19. Use or method according toclaim 2 in which the carrier is glycerol, propylene glycol, or apolyethylene glycol.
 20. Use or method according to claim 3 in which thecarrier is glycerol, propylene glycol, or a polyethylene glycol.